Rivaroxaban, 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl]phenyl)-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide, also known as BAY 59-7939 and marketed under the trade name Xarelto®, is a direct factor Xa Inhibitor and as such an antithrombotic agent having the formula:
(see also J. Med. Chem. 2005, 48, 5900-5908).
Rivaroxaban exists in several polymorphic forms, which have been called “modification I”, “modification II” and “modification III” in WO 2007/039132. The same document also mentions a hydrate, an NMP solvate, a THF-clathrate and an amorphous form of Rivaroxaban. WO 2007/039132 describes that modification II and the amorphous form are to be preferably used in finished dosage forms due to their higher solubility in comparison to modification I. Modification II is described to have a 4-fold higher solubility compared to modification I.
Form I of Rivaroxabin is reported to be of a relatively low solubility, see e.g. the CHMP assessment report Procedure No. EMEA/H/C/000944, and WO2005/060940 mentions that difficulties in oral bioavailability of Rivaroxaban had allegedly to be overcome during the development of an oral dosage form based on modification I. WO2007/039122 mentions as an alternative that melt extrusion and the use of amorphous Rivaroxaban prepared by melting can be of help in improving the oral bioavailability of Rivaroxaban.
It is interesting to note that the preferred, since more soluble, modification II of Rivaroxaban is not employed in the presently marketed oral dosage forms of Rivaroxaban (see e.g. the CHMP assessment report Procedure No. EMEA/H/C/000944), but the less soluble modification I. One possible explanation might be that modification II of Rivaroxaban can not be easily prepared following the processes disclosed in WO2007/039132, in particular when production of modification II, in particular polymorphically pure modification II, is attempted on commercial scale. In WO2007/039132 modification II is prepared by allowing a solution of Rivaroxaban in 1,4-Dioxan to evaporate at 50° C. or by shock-cooling. These process are not easily carried out on large scale at low cost.
There remains thus a need for a novel polymorph of Rivaroxaban with improved solubility properties compared to the sparsely soluble modification I of Rivaroxaban, which polymorphic form at the same time lends itself to facile production at commercial scale, contrary to modification II, preferably at low cost.
Moreover, different crystal forms of one compound may interconvert, that is under certain conditions one crystal form with favorable characteristics may convert to another crystal form with possibly less favorable characteristics. There is thus a need for pharmaceutical compositions comprising rivaroxaban in that very defined polymorphic state which shows favorable characteristics.